Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, and Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
Howard Hughes Medical Institute, UCLA, Los Angeles, CA, USA.
Nature. 2022 May;605(7909):304-309. doi: 10.1038/s41586-022-04670-9. Epub 2022 Mar 28.
Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer's and Parkinson's diseases. FTLD typically presents in 45 to 64 year olds with behavioural changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions with TAR DNA-binding protein (TDP-43) immunoreactivity. Here we extracted amyloid fibrils from brains of four patients representing four of the five FTLD-TDP subclasses, and determined their structures by cryo-electron microscopy. Unexpectedly, all amyloid fibrils examined were composed of a 135-residue carboxy-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. In addition to TMEM106B fibrils, we detected abundant non-fibrillar aggregated TDP-43 by immunogold labelling. Our observations confirm that FTLD-TDP is associated with amyloid fibrils, and that the fibrils are formed by TMEM106B rather than TDP-43.
额颞叶变性（FTLD）是继阿尔茨海默病和帕金森病之后第三常见的神经退行性疾病。FTLD 通常在 45 至 64 岁的人群中出现，表现为行为改变或语言技能逐渐下降。FTLD-TDP 亚型的特点是具有特定的临床症状和病理性神经元包含物，以及 TAR DNA 结合蛋白（TDP-43）免疫反应性。在这里，我们从代表五个 FTLD-TDP 亚型中的四个的四名患者的大脑中提取了淀粉样纤维，并通过低温电子显微镜确定了它们的结构。出乎意料的是，所有检查的淀粉样纤维均由跨膜蛋白 106B（TMEM106B）的 135 个残基羧基末端片段组成，TMEM106B 是一种溶酶体膜蛋白，先前被认为是 FTLD-TDP 的遗传风险因素。除了 TMEM106B 纤维外，我们还通过免疫金标记检测到大量非纤维状聚集的 TDP-43。我们的观察结果证实 FTLD-TDP 与淀粉样纤维有关，并且纤维是由 TMEM106B 而不是 TDP-43 形成的。
